SPECIAL REPORT
Ofatumumab as initial treatment
Switching studies
Long-term efficacy and safety data
Ofatumumab use in Canada
The efficacy of ofatumumab, an anti-CD20 agent administered subcutaneously every four weeks, was shown to be superior to teriflunomide in reducing relapse rates and confirmed disability progression (CDP) in the ASCLEPIOS I/II trials (Hauser et al. N Engl J Med 2020;383:546-557). A subgroup analysis subsequently reported a 50% reduction in annualized relapse rate (ARR), a 46% reduction in 6-month CDP and a 56% reduction in 6-month confirmed progression independent of relapse activity (PIRA) with ofatumumab versus teriflunomide in recently diagnosed, treatment-naïve patients (Gartner et al. Mult Scler 2022;28:1562-1575). This has led to the increasing use of ofatumumab as initial treatment of relapsing multiple sclerosis. The use of ofatumumab as a first-choice agent and its long-term efficacy were among the highlights of this year’s European Committee on Treatment and Research in MS (ECTRIMS) congress, held September 24-26, 2025, in Barcelona, Spain.
Ofatumumab as initial treatment
The AGNOS trial (N=95) examined the use of initial ofatumumab in patients within six months of an MS diagnosis (Hendin et al. ECTRIMS 2025;P428). Overall, 81.1% of patients achieved no evidence of disease activity (NEDA) in months 6-18. Changes in brain volume, cortical grey matter and thalamic volume were similar to what was seen in healthy controls. The most common adverse effects were headache (27.7%), myalgia (26.1%) and fatigue (20.2%).
An EDMUS database analysis (N=319) compared the effectiveness of initial anti-CD20 therapy compared to a treatment escalation strategy (Buissonniere et al. ECTRIMS 2025;P351). ARR at two-year follow-up was 0.09 in the anti-CD20 initiation group compared to 0.3 in the escalation group. The median EDSS at two years was also lower (1.5 vs. 2.5) in the group starting treatment with anti-CD20 therapy; EDSS score was shown to be associated with the time to initiation of an anti-CD20 therapy.
Similar benefits were seen in the real-world CRONOS-MS study (N=310) (Oreja-Guevara et al. ECTRIMS 2025;P1768). Most patients were previously treated; about 37% had received moderate-efficacy DMT and 28% had received a higher-efficacy therapy. At 12 months, ARR was reduced 93.3% with ofatumumab and the EDSS score was stable. No ofatumumab-treated patient had a gadolinium-enhancing T1 lesion and 88% had no new/enlarging T2 lesions at month 12. Notably, the treatment effect was greater in the treatment-naïve subgroup compared to the previously-treated subgroup.
Moreover, the delayed initiation of a higher-efficacy therapy may have important clinical consequences. A real-world study in Argentina (N=176) reported that high-efficacy DMTs were associated with a significantly lower risk of developing PIRA compared to treatment with a low- or medium-efficacy DMT (hazard ratio 7.36) Guarnaschelli et al. ECTRIMS 2025;P1717). The risk of PIRA was also elevated in patients who failed an initial treatment and were subsequently switched to a higher-efficacy DMT (HR 2.36).
Switching studies
The ARTIOS phase IIIb study (N=562) evaluated the efficacy of ofatumumab in patients (mean age 36 years) with breakthrough disease during treatment with an oral fumarate or fingolimod (Bove et al. ECTRIMS 2025;P791). Overall, 90.9% achieved NEDA in year 2; Gd-enhancing lesions were reduced 98.1% from baseline; and ARR was low (0.06). Mean serum IgG levels remained above the lower limit of normal (LLN) in 97.9% of patients at all timepoints.
A separate study (N=280) examined the efficacy of ofatumumab when started within two months after natalizumab discontinuation (Zolin et al. ECTRIMS 2025;P877). There was no breakthrough disease (relapses, MRI activity) following natalizumab discontinuation and no change in EDSS score, suggesting that timely initiation of ofatumumab may prevent rebound disease activity after natalizumab discontinuation.
Long-term efficacy and safety data
The long-term efficacy and safety of ofatumumab is being evaluated in the ongoing ALITHIOS extension of the ASCLEPIOS I/II trials and results at seven years are now available (Hauser et al. ECTRIMS 2025;P804). In the continuous ofatumumab group, ARR was 0.023 and there was almost complete suppression of MRI activity (NEDA rate 95.0%) at seven years. Results were similar in teriflunomide-treated patients after switching to ofatumumab (ARR 0.048, NEDA 93.8%). The incidence of malignancies (0.31/100 patient-years) and serious infections (1.37/100 PY) remained low during chronic drug exposure. Mean IgG levels were >LLN in 96.8% of patients at all timepoints in patients receiving uninterrupted treatment with ofatumumab (Wiendl et al. ECTRIMS 2025;P932).
Similar results were reported for the subgroup of recently-diagnosed patients who initiated treatment with ofatumumab (Hauser et al. ECTRIMS 2025;P805). ARR was 0.024 and 95.8% achieved NEDA in the continuous ofatumumab group at seven years. The incidence of serious infections was 0.59/100 PY. Serum IgG levels were >LLN in 97.6% at all assessments.
A separate analysis examined serious infections during chronic ofatumumab exposure (Ziemssen et al. ECTRIMS 2025;P812). Cumulative drug exposure at seven years was 9258.2 PY. The most common serious infections were COVID-19 (2.59%), urinary tract infections (1.02%), lower respiratory tract infections (excluding COVID-19) (0.96%) and appendicitis (0.76%). The annualized rate of serious infections (excluding COVID-19) remained stable: 0.013 in year 1, 0.011 in year 3, and 0.023 in year 7.
Ofatumumab use in Canada
The CAPES observational study evaluated data for the cohort of patients in Canada enrolled in the GO patient support program for ofatumumab (N=5448) (Grant et al. ECTRIMS 2025;P1793). Mean age was 41.2 years (10% aged >55 years); 72.9% were female; and 37.1% were treatment-naïve at ofatumumab initiation. The most common prior therapies were dimethyl fumarate (19.1%), glatiramer acetate (15.2%), teriflunomide (13.8%) and ocrelizumab (12.2%). The overall rate of treatment persistence with ofatumumab was 96.9% at one year, and 92.3% at three years. Persistence rates were similar between patients with and without prior DMT exposure. Discontinuation rates due to lack of efficacy (0.1%) or non-adherence (0.1%) were low. A similarly high persistence rate (93.3% at two years) was reported in an MSBase analysis of an Australian cohort receiving ofatumumab (Butzkueven et al. ECTRIMS 2025;P1736).